Relevance: Marijuana is the most commonly used illicit drug in the U.S., and 6 percent of high school seniors report using marijuana >20 times per month. Neuromaturation continues during adolescence in the form of gray matter decreases and white matter increases, including in regions with dense distributions of cannabinoid receptors (e.g., frontal lobe, hippocampus, striatum, and cerebellum). However, few studies have examined the relationship between heavy marijuana use during adolescence and subsequent brain development. Longitudinal studies are essential to determine if previously observed abnormalities predate cannabis use or are caused by cannabinoid exposure. Description: In this application, we propose to recruit 78 adolescents to add to a cohort of 90 adolescents recruited in project R21 DA15228 (PI: Tapert), and follow these 168 teens with the same neuropsychological tests, functional magnetic resonance imaging (FMRI; working memory, inhibition, and learning tasks), MRI (to examine brain volume), and diffusion imaging (to probe white matter integrity) 1.5 and 3 years after the initial assessment. Brief interviews will be conducted each 6 months over the 3-year follow-up period to assess marijuana, alcohol, nicotine, and other drug use and academic involvement. Participants will be 126 heavy marijuana users and 42 non-users, recruited through two local school districts using the same approach as in R21 DA15228. At baseline, all participants will be age 16-18, free from psychiatric, learning, neurological, and medical disorders, and with limited exposure to alcohol, nicotine, and other drugs. Among users, late onset (after age 16) current users, early onset (less than or equal to 15) current users, and early onset (less than or equal to 15) former users will be targeted for recruitment. Prior to each imaging session, youths will undergo a 28-day monitored abstinence period by providing urine samples every 3-4 days and a hair sample for drug toxicology (as in R21 DA15228). Aims: Aims of the current application are to: (1) replicate preliminary findings of CNS differences between chronic heavy marijuana users and demographically similar non-users after 28 days of abstinence; (2) determine whether early onset (as opposed to duration) of heavy marijuana use is associated with abnormal CNS functioning; (3) determine if frequency and intensity of marijuana use predicts changes in brain imaging and cognitive test measures over a 3-year period; and (4) evaluate if FMRI response patterns during executive functioning tasks can predict subsequent substance use. All analyses will control for premorbid factors (i.e., family history of substance use disorders and personality), educational involvement (i.e., attendance), and other substance use (i.e., alcohol, nicotine, and other drugs). [unreadable] [unreadable] [unreadable]